Midfacial hypoplasia is a growth deficiency that can lead to severe deformity with impairment of feeding and breathing. Current treatments include drastic surgeries that reposition bones but do not promote growth. This project assesses the potential of a less invasive mechanotherapeutic strategy for preventing the early fusion of hypoplastic midfacial sutures. Cyclic loading is anabolic for sutures. As a working hypothesis, we propose that cyclic loading preserves patency by promoting the proliferation of sutural cells, and that in the central zone these cells are inhibited from becoming osteoprogenitors. The proposed mechanism by which this occurs is that the central zone of the suture becomes hypoxic as cyclic loading disrupts blood flow. Hypoxia then leads to mesenchymal proliferation, angiogenesis, and matrix remodeling; these events inhibit cells from osteodifferentiation until they move out of the central zone into the bone-forming zones. In this way mechanotherapy would both preserve sutural patency and promote bone growth. The Aims of the project will test the clinical validity of the cyclic loading concept, the working hypothesis, and the proposed vascular mechanism. It will serve as proof of principle for future investigations of molecular mechanisms and the development of new treatment modalities. Minipigs are similar to humans in craniofacial physiology, and their sutural mechanics are well documented. We will employ a unique minipig breed with severe midfacial hypoplasia related to hypoplastic, early fusing facial sutures. Cyclic or sham loads will be applied to sutures and the resulting strains measured using strain gages. Specific Aim 1 will test whether the hypoplastic sutures increase their growth in response to the treatment. Specific Aim 2 will test the working hypothesis by determining sutural proliferation/apoptotic rates and establishing whether osteoprogenitors are downregulated in the central zone. Specific Aim 3 will test the predictions of the vascular mechanism that loading will increase vascularity and disorganize the sutural ligament. This research will advance our understanding of the biological regulation of suture patency and elucidate the pathogenesis of midfacial hypoplasia. If the concept, working hypothesis and/or the vascular mechanism are supported by the findings, our long-term goal will be to develop mechanical and pharmacological therapies for this serious disorder.